A prominent theory regarding the development of epileptic hyper-synchronization in human and animal models of temporal lobe epilepsy proposes a key role for the specific down-regulation of the expression of the KCC2 transporter in subicular pyramidal cells. As KCC2 is essential to maintain the low intracellular chloride concentrations required for hyperpolarizing GABAergic signaling, loss of KCC2 expression would impair GABAergic inhibition and trigger a series of events leading to the emergence of subicular-initiated interictal activity. Furthermore, interictal discharges coupled to synaptic plasticity would result in interictal- ictal transitions and spread hyper-excitability to extra-hippocampal regions. In summary, if the essential aspects of this KCC2-based mechanistic theory of epileptogenesis were correct, the selective pharmacological reduction of KCC2 transporter activity in a nave subiculum should be sufficient to generate epileptiform activity ranging from interictal-like to, possibly, full ictal-like events. Although this prediction was supported by computational modeling, direct experimental evidence has not yielded definitive results. Our preliminary data show that the application of highly selective KCC2 antagonists on isolated mini-slices of the mouse subiculum generate synchronous interictal-like bursting that depends on depolarizing GABAergic signaling, but are not, apparently, sufficient to trigger ictal-interictal transitions. We will take advantage of a variety of state of the art techniques (simultaneous patch-clamp recordings from synaptically coupled and uncoupled cells, optogenetic control of specific neuronal populations, and high resolution anatomical reconstructions) to investigate the impact of this type of pharmacologically- induced epileptiform activity in subicular mini-slices. We will explore its consequences on intrinsic and synaptic plasticity, reveal the underlying mechanisms played by different interneuron subtypes, and explore whether additional epileptogenic changes and/or synaptic input from extra-subicular regions are necessary to drive interictal-like to ictal-like transitions.